Alzheimer?s disease (AD) is a devastating neurodegenerative disease affecting approximately 5.3 million people in the US. Currently, there are no blood or laboratory tests linked to the pathology that can provide a conclusive early diagnosis of AD. The lack of such tests has hampered the development and successful use of potentially beneficial AD therapies. In view of this, the broad, long-term objective of the proposed study is to develop accurate and reliable blood tests that can be used for detection of preclinical and prodromal AD (i.e., at mild cognitive impairment, MCI) as well as for monitoring AD progression from the preclinical stage to MCI and later AD stages. Our previous studies using human protein microarrays have shown that all humans possess thousands of autoantibodies in their blood and that individual autoantibody profiles are influenced by the presence of disease. We have exploited disease-specific changes in autoantibody profiles to identify biomarkers useful for diagnosing patients with prodromal AD at MCI and mild-moderate disease stages as well as early- and moderate-stage Parkinson?s disease with high sensitivity and specificity. In this proposed study, we will utilize autoantibodies as blood-based biomarkers and human protein microarrays as a testing platform to validate the selected MCI biomarkers with an independent patient cohort to test the ability of these biomarkers to identify patients at MCI and preclinical stages of AD. The following aims are proposed: Specific Aim #1 is to carry out a replication or validation study of early detection of AD at the prodromal (MCI) stage in subjects with low CSF Abeta42 levels and confirm disease stage- and disease-specificity using serum samples from an independent cohort of ADNI MCI subjects who subsequently transitioned to AD. To test the linkage between the efficacy of MCI biomarkers and early AD pathology, Specific Aim #2 will determine the effects of CSF Abeta42 level and cortical amyloid load as pathological indicators of early AD pathology on the overall accuracy, including disease staging and disease specificity, of the MCI biomarker panel. As a result of the high overall accuracy of our MCI biomarker panel in distinguishing MCI subjects with low CSF Abeta42 levels from controls shown in our previous study, Specific Aim #3 is to determine the utility of the prodromal AD (MCI) biomarkers for preclinical detection of AD. Here, the MCI biomarker panel will be probed using sera from subjects who originally enrolled in ADNI as healthy controls, but later transitioned to MCI or full-blown AD. Controls will be ADNI subjects who also enrolled as healthy controls but showed no clear signs of cognitive decline over the same time period. The development of an accurate, relatively noninvasive, inexpensive and early blood-based diagnostic test for AD will be of great benefit to patients afflicted with this disease, since early treatment greatly increases the likelihood of a successful outcome. In addition, it would facilitate earlier enrollment into AD clinical trials, and would enable monitoring of AD progression in patients who are under treatment by their physicians or participating as subjects in clinical trials for new potential therapeutics.